A staggering estimated 317,000 new cases of prostate cancer will be diagnosed and over 45,000 prostate cancer deaths will occur this year in the United States making prostate cancer the most frequently diagnosed and second leading cause of cancer mortality in men in the United States. Deaths from prostate cancer in the United States are increasing every year by 2%-3% because fewer men are dying from cardiovascular disease. (Walsh, 1994) Unfortunately, the age-specific mortality rate for prostate cancer continues to rise in spite of earlier detection by serum PSA or current prostate cancer treatment modalities. Moreover, at the time of diagnosis the majority of men will have prostate cancer at a stage for which there is no cure and the prognosis is dismal.
African-American men have the highest prostate cancer mortality rates of any population in the world, twice that of white men 65 years or older. Furthermore, survival rates in the United States for all stages of prostate cancer diagnosed between 1983 and 1990 was 81.3% for Whites, but only 66.4% for Blacks. Of all prostate cancer deaths in 1991, Blacks accounted for 15.8%, Hispanics for 2.5%, and American Indians, Chinese, and Japanese for less than 1%. The general United States population is 75% White, 12% African-American, 8% Hispanic, and 3% Asian.
The standard method of treatment for the past 50 years has been castration, surgical or chemical, but the prostate cancer has eventually become androgen-independent, resumed growth, and killed the patient. Clearly, better androgen blockade is not the answer for treating prostate cancer. Rather, treatment efforts should focus on modifying the mutations that lead to prostate oncogenesis. Although some genetic markers can at least partially predict patients who are likely to develop metastatic disease, it is still impossible to predict absolutely patient prognosis and response to therapy. (Walsh, 1994; Carter et al., 1990) Thus, even well implemented early detection programs may not completely eradicate the eventual development of metastasis in some patients.
The molecular biology of prostate cancer is poorly understood. Attempts to develop animal models of prostate cancer with transgenic mice have been less successful than for animal models of other cancers such as breast cancer. (Mulders et al., 1990; Oesterling, 1991; Jurincic et al., 1990; Hamdy et al., 1992; Pang et al., 1995; Matuo et al., 1989; Dodd et al., 1983; Greenberg et al., 1994; Greenberg et al, 1995; Tutrone et al., 1993; Matsui et al., 1990; Halter et al., 1992; Cato et al., 1989; Choi et al., 1987; Tutrone et al., 1993; Matsui et al., 1990; Halter et al., 1992; Muller et al., 1990) This has presumably happened because little is known about prostate-specific promoters and because study of oncogenes and tumor suppressor genes have yielded few clear-cut candidate genes for prostate cancer.
Inherited mutations in BRCA1, (Hall et al., 1990; Miki et al., 1994) confer lifetime risk of breast cancer greater than 80% and increased risk of ovarian cancer. (Newman et al., 1988; Ford et al., 1994). Multiple lines of evidence suggest that BRCA1 is a tumor suppressor for the following six reasons:
(1) Most (87%) inherited mutations truncate the BRCA1 protein, leading to loss of BRCA1 function. (Breast Cancer Information Core, 1996) PA1 (2) The wild-type allele is lost from &gt;90% of breast and ovarian tumors from patients with inherited BRCA1 mutations. (Friedman et al., 1994; Neuhausen et al., 1994; Smith et al., 1992) PA1 (3) BRCA1 expression is reduced in breast and ovarian tumors from patients not selected for family history. (Thompson et al., 1995) In such tumors, somatic inactivation of BRCA1 may occur through mechanisms such as large deletions or epigenetic silencing of BRCA1 expression, rather than point mutation. (Futreal et al., 1994; Cropp et al., 1993; Saito et al., 1993; Cliby et al., 1993; Russell et al., 1990; Takahashi et al., 1995; Yang-Feng et al., 1993) PA1 (4) Inhibition of BRCA1 expression with antisense oligonucleotides leads to accelerated growth of normal and malignant mammary epithelial cells. (Thompson et al., 1995) PA1 (5) Overexpression of BRCA1 inhibits growth of breast and ovarian cancer cell lines derived from patients not selected for family history. (Holt et al., 1996) PA1 (6) Transfection or infection of MCF-7 breast cancer cells with the wild type BRCA1 gene inhibits tumor development and suppresses growth of established tumors in nude mice. (Holt et al., 1996) The biochemical mechanism responsible for growth inhibition and tumor suppression by BRCA1 involves secretion, since BRCA1 has sequence homology and functional analogy to the granin protein family. Wild type BRCA1 is localized to the Golgi; (Jensen et al., 1996) and wild-type BRCA1 is also present in the nucleus, although reports differ in the relative amounts of nuclear versus cytoplasmic protein. (Chen et al., 1995)
There has been no affirmative suggestion of a treatment of prostatic cancer comprising a therapeutic application of the BRCA gene family, and particularly comprising a therapeutic application involving BRCA1. This is true despite certain epidemiological, genetic, and biological observations in the art, including the following four observations: (1) Breast and prostatic cancer, and ovarian and prostatic cancer, are associated in families, (Jishi et al., 1995; Anderson et al., 1993; Sellers et al., 1994; Tulinium et al., 1994) although the association is not observed in families in which index cases were patients with prostatic cancer (rather than breast or ovarian cancer). (Isaacs et al., 1995) (2) Inherited mutations in BRCA1 have been observed in prostatic cancer patients, both in families at high risk of breast and ovarian cancer (Ford et al., 1994; Friedman et al., 1994; Struewing et al., 1995) and in isolated patients. (Langston et al., 1996) (3) Prostatic tumors are frequently hemizygous for markers in or near BRCA1. (Williams et al., 1996; Gao et al., 1995; Brothman et al., 1995; Gao et al., 1995) (4) The malignant phenotype of the human prostatic cancer cell line PPC-1 was suppressed by transfer of an -30 Mb portion of chromosome 17 containing BRCA1. (Murakami et al., 1995). Additionally, although the 30 Mb portion of chromosome 17 contained BRCA1, it also contained numerous other genes and included a region proposed to contain a different tumor suppressor gene.
Given the prevalence of prostate cancer, what is needed, then, is an effective therapy for prostate cancer that addresses the disease at a molecular genetic level. Despite attempts to characterize the molecular biology of prostate cancer, such a therapy is lacking in the prior art.